Process for the manufacture of 3beta-hydroxy-5beta-cardenolides

ABSTRACT

MANUFACTURE OF 3B-HYDROXY-5B-CARDENOLIDES OF THE 14DEHYDRO OR 14B SERIES BY TREATMENT OF 3-DETO-5B-CARDENOLIDES WITH IRIDIUM (IV)-HYDROCHLORIC ACID, ITS SALTS OR IRIDIUM (III)-CHLORIDE IN THE PRESENCE OF TRIALKYL-PHOSPHITE.

United States Patent "ice 3,657,228 1 PROCESS FOR THE MANUFACTURE OF Sfi-HYDROXY-Sfi-CARDENOLIDES Kurt Radscheit, Kelkheim', Taunus, Werner Fritsch, .Neueuhain,"Taunus, and Werner Haede and Ulrich Stache,Hofheim, Tauuils, Germany, assignors to Farbwerke Hoechst Aktiengesellschaft vormals Meister Lucius & Bruning, Frankfurtam-Main, Germany- No Drawing. Filed Nov. 12, 1970, Ser. No. 89,098

Claims priority, application Germany, Nov. 14, 1969,

Int. Cl. C07c 173/00 US. Cl. 260 -92395 7 1 Claim ABSTRACT OF THE DISCLOSURE Manufacture of 3fi-hydroxy-5fi-cardenolides of the 14- dehydroor 14p series by treatment of 3-keto-5B-cardenolides with. iridium(lvyhydrochloric acid, its salts or iridium(IID-chloride in the presence of trialkyl-phosphite.

Belgian Pat. No. 707,326 describes a process for the manufacture of 3fi hydroxy ifi-cardenolides, 'wherein 3- keto-Sfl-cardenolides,are first reduced by means of complex metal hydrides'to yield the corresponding 3a-hydroxy-compounds and the latter are converted by Walden inversion into the 313-cardenolides.

It has also been proposed to prepare SB-hydroxy-Sficardenolides by reducing 3-keto-5;8-cardenolides (by means of aluminium alcoholate according to Meerwein-Ponndorf and separating the 3a-hydroxy-cardenolides that have formed simultaneously in about the same quantity, dehydrogenating them again to obtain S- ketO-SB-cardenolides, whereupon these may be subjected again to the Meerwein-Ponndorf reduction.

The present invention provides a simple and smoothly proceeding process for the manufacture of 3/3-hydroxy- S it-cardenolides of the 14dehydroor 14,8-series, wherein corresponding 3 keto-/3-cardenolides are treated with iridium(IV)-hydrochloric acid, its alkali metal or ammonium salts or iridium(III)-chloride in the presence of trialkyl phosphite and lower alcohols.

The process proceeds, for example, according to the following reaction scheme:

P(OOH3) I IV CH2 CO CH H H0 91% Y Li H Patented Apr. 18, 1972 As starting substances, for example 3-keto-5fl-carda-l4, 20(22)-dienolide or 3-keto-14fl-hydroxy-5/3-card-20(22)- enolide may be used.

The reduction is efiected in the usual manner by heating the 3-keto-5fi-cardenolide with the soluble iridium (III)- or (IV) -salt, of which catalytic amounts are preferably used, in a low molecular alcohol in the presence of trialkyl phosphite, for a prolonged period of time, i.e. for about 1 to 5 days, preferably for 50 to 150 hours, under reflux to the boiling temperature. As lower alcohols, it is advantageous to use propanol-Z which may advantageously contain up to 10% of water. As trial'kyl phosphite, it is advantageous to use trimethyl phosphite, at least in a stoichiometrical amount. It is possible to operate with or without addition of a small amount of mineral acid. If iridium(III)-chloride is used for derivatives of the 14-dehydro series, the addition of a small amount of concentrated hyrochloric acid is of advantage.

The 3-keto-5 3-cardenolide to be reduced may be added to the reducing mixture either immediately or after some hours (up to 15 hours). When the reaction is complete, the reaction mixture is removed from the aqueous solution, for example by filtration with suction or extraction with organic solvents. 1

The advantage of the process of the invention over the process described in Belgian Pat. No. 707,326 resides in the fact that several reaction stages can be omitted. In the known process, first the reduction is effected, then the esterification is carried out with p-toluene-sulfochloride and the resulting compound is then rearranged (Walden inversion) with potassium fonnate. The total yield is about 40%. In contradistinction thereto, in the process of the invention the reaction with p-toluene-sulfochloride and the subsequent Walden inversion are not necessary and the yields obtained are higher than The reduction of 3-keto-androstaneand 3-keto-pregnane derivatives to the corresponding axial 3,B-hydroxy compounds with iridium(IV)-hydrochloric acid is described in J. Chem. Soc. (C)(19 69), pages 11653-1659. In the light of this literature reference, the application of the same reducing agent to steroids which contain the sensitive org-unsaturated lactone ring appeared very questionable. As regards the known reaction, only the reduction of saturated keto-steroids had been described, thus an undesired action of the reagent on double bonds, for example on those in the 14,15-p0siti0n of steroids, had to be expected. 'For example, a partial conversion of the thermodynamically unstable cardenolides of the 14-dehydroor 14fl-series into the more stable 8(14)- or 8(9)- dehydro-cardenolides or -isocardenolides could have taken place. In addition, it is known from the mentioned literature reference that, for example pregnane-ZOB-ol or 21- hydroxy-pregnane-ZO-one is attacked by the reagent in a partly unsurveyabel manner. The lateral chain of pregnane-20-one, on the other hand, undergoes epimerization in the 17-positiou.

The process according to the invention permits, in unexpected manner, the manufacture in a smooth reaction and with good yields of derivatives of the important 35- tie- .2 8 Y.

series of the digitoxigenin'steroids; there is obtained, 'in-'-' the 14,8-hydroxy series, either directly the highly cardioactive digitoxigenin or its pre-stage, i.e. the 14,20(22)- dienolide which can be converted by known processes into digitoxigenin.

The following examples illustrate the invention:

EXAMPLE 1 3 fl-hydroxy-SB-carda- 14,20 22) -dienolide 20 ml. of trimethyl-phosphite and 500 mg. of iridium- (IV)-hydrochloric acid were introduced into a stirred suspension of g. of 3-keto-5 3-carda-14,20(22)-dienolide in 250 ml. of 90% propanol-2. The reaction mixture was then heated for 62 hours to the boil, while stirring and cooling of the reflux. After 49 hours, the whole starting material had dissolved. At the end of the total reaction time, the clear almost colorless solution was stirred into 1 liter of water. The reaction product that had precipitated was filtered off with suction, washed with water and taken up in methylene chloride. After washing with water and drying over sodium sulfate, it was concentrated to dryness under reduced pressure. After recrystallization from a mixture of methylene chloride and methanol, 9.15 g. of 3 8-hydroxy-5fi-carda-14,20(22)-dienolide melting at 195-199 C. (corrected) were obtained. [a] =-28; [u] =160 (chloroform 0.5%

About 400 mg. =4%) of 3a-hydrOXy-Sfl-carda-14,20 (22)-dieno1ide melting at 196 C. could be obtained from the mother liquors by chromatography.

* 1 "EXAMPLEZ 3,6,14B-dihydroxy-5B-carda-20(22)-eno1ide (Digitoxigenin) 10 ml. of trimethyl-phosphiteand 250 mg. of iridium- (IV)-hydrochloric acid were introduced into a solution of 5.0 g. of 3-keto-14,8-hydroxy-5B-card-20(22)-enolide in 250 ml. of propanol-Z strength). The reaction mixture was then heated for hours to the boil under reflux. It was then cooled rapidly and stirred into 400 ml. of water and extracted with chloroform. The extract was washed with water until neutrality, dried over sodium sulfate and concentrated to dryness under reduced pressure. After recrystallizationfrom a mixture of acetone and petroleum ether, 4.25 g. of digitoxigenin were obtained. Melting point: 240-242 C. [a] =18.1 (in CHCl What we claim is:

1. Process for the manufacture ofBB-hydroxy-Sfi-cardenolides of the 14-dehydroor 14,8-series, wherein corresponding 3-keto-5B-cardenolides are treated with iridium(IV)-hydrochloric acid, its alkali metal or ammonium salts or iridium(III)-chloride in the presence of trialkylphosphite and lower alcohols.

References Cited Jour. Chem. Soc. (1969), pp. 1653-1659.

ELBERT ROBERTS, Primary Examiner 

